In Silico Design of New Inhibitors Against Hemagglutinin of Influenza

Abstract

The RNA virus influenza A is a serious public health problem, with epidemics resulting in more than 250 000 deaths every year. A protein cavity was identified on the HA2 subunit of the hemagglutinin responsible for the entry of the virus into the host cell by endocytosis. The binding of a ligand in this zone rich in invariant residues and synthetic lethal couples could prevent therapeutic escape and inhibit the conformational change at pH = 5 which is necessary to initiate the membrane fusion in the endosome. Two pentapeptides, a linear peptide (EQRRS) and a cyclic peptide (DQRRD), have been proposed as potential ligands. Complex stability and the interactions between the ligand and the protein have been studied with the help of molecular dynamics and quantum chemistry methods. A high stability of the interactions has been obtained for these two ligands at both pH = 7 and pH = 5. Indeed, these two peptides present two cooperative modes of action that should prevent the conformational change at the origin of the spring-loaded mechanism at pH = 5, (1) mechanical because they are docked on HA2 and (2) electronic because they modify the protonation states of key residues in the loop. This study thus paves the way toward the development of peptide ligands that can inhibit the membrane fusion process.

The Symmetric Difference Distance: A New Way to Evaluate the Evolution of Interfaces along Molecular Dynamics Trajectories; Application to Influenza Hemagglutinin

“…Starting from an initial conformation at time t 0 , the MD simulation at pH = 7 generated 40 conformations, at times t 1 , t 2 , ..., t 40 , and similarly, the MD simulation at pH = 5 generated 40 conformations, the time step between two conformations being 0.5 ns [8]. Thus, there was a total of 41 conformations for each of these two MD simulations.…”

“…After having observed that the HA conformation remains stable over the 40-ns simulations, we needed to define a mean conformation for docking purposes. Indeed, considering such an average structure in the course of a docking simulation, rather than a structure determined from X-ray diffraction experiments, enables us to take into account the relaxation of the protein in the solvent, at T = 310 K [8]. We defined this mean conformation with the algorithm described in [14]: it is the one that minimizes the sum of the squared distances to all other conformers.…”

“…In a recent modeling study to design new inhibitors against HA, two Molecular Dynamics (MD) simulations were performed, one at pH = 7 and one at pH = 5, this acidic pH being the one inducing a conformational change [8]. A motivation of this previous study was to compare the simulations at both pH values.…”

“…Starting from an initial conformation, 40 conformations were extracted every 0.5 ns for two performed simulations (see [8] for technical details about the protocol). The problem considered here is to evaluate, for each set of 41 conformations, the dissimilarities between pairs of conformations.…”

Peptide Inhibitors of Viral Membrane Fusion

“…Peptides that could bind a "protein cavity" in the HA2 subunit of HA were designed by Perrier et al, 55 based on molecular dynamics and quantum chemistry calculations. Two pentapeptides were identified that interacted with HA2 with high stability at both pH 7 and 5.…”